Androgen receptor CAG repeat polymorphism is associated with cognitive function in older men.

BACKGROUND: Androgen receptors are located throughout the brain, especially in regions involved with learning and memory. Different lengths of a CAG (glutamine) repeat polymorphism in exon 1 of the androgen receptor gene may influence androgen action, with longer repeat lengths conferring decreased androgen sensitivity. METHODS: We sought to determine if this CAG polymorphism was associated with cognition in older men. RESULTS: Among 301 community-dwelling white men (mean age, 73.0 +/- 7.1), greater CAG repeat length was associated with lower scores on three cognitive tests (p <.05 for all). In addition, 12 participants (9.8%) had cognitive impairment in the low tertile of CAG repeat length whereas 29 (16.3%) had cognitive impairment in the two higher tertiles (odds ratio = 1.8; 95% confidence interval =.9-3.7). CONCLUSIONS: Research should be directed at identifying the mechanism for this association and to determine if treatment with testosterone prevents cognitive decline.     

Nonprogressive juvenile-onset spinal muscular atrophy: A clinico-radiological and CAG repeat study of androgen receptor gene

BACKGROUND: Occurrence of nonprogressive juvenile-onset spinal muscular atrophy (SMA) predominantly in males suggests a possibility of X-linked disorder but there is no such report addressing this problem. AIMS: To evaluate CAG repeat expansion of androgen receptor (AR) gene in patients with nonprogressive juvenile-onset SMA. SETTING: Tertiary medical teaching institute. SUBJECTS AND METHODS: Patients fulfilling the diagnostic criteria of nonprogressive juvenile-onset SMA were included. Detailed clinical evaluation and pedigree charting were done in all. Nerve conduction study, electromyography and cervical spinal MRI were carried out. From peripheral venous blood, DNA was separated and AR gene CAG repeat exon polymorphism was assayed using polymerase chain reaction (PCR) in conjugation with genotyping and Gene scan soft ware. Number of CAG repeats was compared with normal controls. RESULTS: 25 patients with nonprogressive juvenile-onset SMA from 24 families were included and their mean age was 22.2 years. Age at the time of disease onset ranged between 15 and 30 years with a mean duration of illness 2.6 years. None of the patients had testicular atrophy or gynecomastia. C7-T1 myotomal wasting and weakness although was unilateral to begin with but became bilateral in 16 and 4 more patients had evidences of subclinical involvement of the other side as revealed by EMG. Spinal MRI revealed cord atrophy at C6-8 vertebral level in 16 patients. CAG repeat study of AR gene was carried out in 16 patients. The number of CAG repeats in patients ranged between 15 and 39 (median 21) which were within the normal range. CONCLUSION: Abnormal CAG repeat expansion of AR gene is not found in patients with nonprogressive juvenile-onset SMA.     

Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men.

BACKGROUND: Testosterone (T) level declines progressively with age. Psychiatric symptoms of T deficiency (e.g., dysphoria, fatigue, irritability, low libido) are also symptoms of depression, and appear to be variably expressed. METHODS: We assessed independent measures of hypothalamic-pituitary-gonadal axis functioning, i.e., total T level and androgen receptor (AR) CAG repeat length (CAG RL), a genetic trait marker associated with AR function; and depression (diagnosed by above-threshold score on the Center for Epidemiologic Studies-Depression Scale [CES-D]) in 1000 men (mean age = 62.6 years; SD = 8.3) who participated in the Massachusetts Male Aging Study. RESULTS: There were 110 (11%) men with "depression" (CES-D score > or = 16) in the analysis sample. Neither total T level nor CAG RL was associated with depression in bivariate analyses. Among men with shorter CAG RLs, the percentage of men with depression was 21.6% in the lowest subgroup of total T (defined by quintiles) and 4.2% in the highest subgroup of total T. This was confirmed in simple logistic regression models with depression as the dependent variable and continuous total T as the predictor, run separately within the three CAG RL subgroups: depression was significantly and inversely associated with total T in men with shorter CAG RLs but not in men with moderate and longer CAG RLs. CONCLUSIONS: CAG isotype, a genetic trait marker of androgen receptor function, may mediate the expression of the central nervous system effects of T deficiency in men.     

Distribution of androgen receptor CAG repeat polymorphism in Chinese schizophrenia and its correlation with age at onset

The action of androgens is mediated by the androgen receptors (ARs), which are located throughout the brain. The AR gene is implicated in the pathogenesis of schizophrenia because male siblings with schizophrenia share alleles at this gene at a rate higher than chance predicts, and differences in sex hormone function may explain the gender difference in schizophrenic manifestations. Since the shorter alleles of the AR CAG repeat polymorphism are associated with increased gene expression, we tested the hypothesis that the AR CAG repeat variant confers susceptibility to schizophrenia using a sample of 225 people with schizophrenia and 247 normal controls. Using the median AR repeat length in the normal group as the arbitrary cut-off point (<24 and >25 CAG repeats), the results show no association between the AR repeat length and schizophrenia in either sex. Furthermore. AR CAG repeat length did not affect the age of symptom onset in the schizophrenic population. Our findings suggest that it is unlikely that the AR CAG repeat polymorphism plays a major role in the pathogenesis of schizophrenia. Nevertheless, given that androgens affect cognitive function, violent behavior and mood, the effect of the AR CAG polymorphism on the clinical manifestations of schizophrenia may warrant further exploration.     

Associations between sex steroid hormone levels and depressive symptoms in elderly men and women: results from the Health ABC study

INTRODUCTION: Sex steroid hormone levels decline with age and in some studies this decline has been linked with depressive symptoms. This study investigates the association between total testosterone, free testosterone, and DHEAS levels with depressive symptoms in a well-functioning elderly population. METHODS: Data are from 2855 well-functioning elderly men and women, 70-79 years of age, participating in the Health, Aging, and Body Composition study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression scale. Total testosterone, free testosterone, and DHEAS levels were assessed after an overnight fast. RESULTS: In men and women, DHEAS levels and depressive symptoms were inversely associated after adjustment for covariates (men: beta=-0.059, p=0.03, women: beta=-0.054, p=0.05). In addition, free testosterone levels in women, but not in men, were inversely associated with depressive symptoms (adjusted beta=-0.079, p=0.004). Men, but not women, in the lowest total testosterone quartile reported significantly more depressive symptoms than men in the other total testosterone quartiles (adjusted beta=-0.166, p=0.04). DISCUSSION: Our study is consistent with the idea that testosterone and DHEAS levels may play a role in mechanisms underlying depressive symptoms in old age.     

X-Linked recessive bulbospinal neuronopathy: Clinical phenotypes and cag repeat size in androgen receptor gene

Clinical phenotypes and the CAG repeat size of the androgen receptor gene were assessed in 95 Japanese patients with X-linked recessive bulbospinal neuronopathy. There was an age- and duration-dependent deterioration of muscle strength, ADL scores, and plasma creatine kinase levels. However, there was no correlation between the presence or absence of gynecomastia or diabetes mellitus and the age at onset or duration of illness. Correlations were present between the CAG repeat size and the age at onset (P < 0.0001) as well as the presence or absence of gynecomastea (P < 0.05). Muscular weakness and ADL scores were also correlated with the CAG repeat size only when they were adjusted by the age at examination not by the duration of illness. These findings suggest that CAG repeat size is one of the determinant factors of disease progression. However, extensive variation in phenotypic severity in patients with the same size of CAG repeat was present even among the siblings, suggesting that other factors than CAG repeat size influence the phenotypic manifestation. The average gain of CAG repeat size expansion was a 1.4 repeat in paternal transmission which was more unstable than that in maternal transmission, but the magnitude of the expansion in paternal transmission was much smaller than is presently known for other diseases in which CAG repeat expansion is the responsible gene defect. © 1995 John Wiley & Sons, Inc.     

Saliva testosterone and cortisol in male depressive syndrome,a community study. The Sudurnesjamenn Study

Abstract

Introduction: The association between testosterone levels and depression is unclear. The relationship has been described as complex, i.e. more U (J)-shaped than linear in some previous studies. Aim: The primary aim of this study was to examine the relationship between saliva testosterone level variations and different levels of male depressive symptoms in a community sample. The secondary aim was to investigate whether simultaneous testing of evening cortisol and testosterone improved the detection of depression. Methods: In a community study, 534 males were screened, using the Beck Depression Inventory (BDI), the Gotland Male Depression Scale (GMDS) and the Montgomery–Åsberg Depression Rating Scale (MADRS). Those with signs of depression (n = 65) and randomly selected controls (n = 69) had psychiatric evaluation for depressive disorder. In a sub-sample (n = 51) saliva testosterone was measured twice on a single day. Results: Testosterone morning values were significantly higher than evening values (236 vs. 145 pg/ml, P = 0.009). Evening testosterone was significantly higher in depressive males, according to both MADRS (P = 0.028) and BDI (P = 0.036). Having depression increased the likelihood of being in the highest third of testosterone levels (BDI P = 0.021; MADRS P = 0.018). Positive correlation was between total BDI score and elevated evening testosterone with and without psychotropics (P = 0.017; P = 0.002). Correlation was between elevated evening cortisol and evening testosterone levels (P = 0.021) though simultaneous testing did not increase specificity of detecting depression. Conclusion: Evening saliva testosterone measurements seem the most informative, as they correlate with male depressive syndrome. Simultaneous testing for evening cortisol and evening testosterone levels did not increase specificity for clinical diagnosis of depressive disorder.     

Sleep and sadness: exploring the relation among sleep,cognitive control,and depressive symptoms in young adults

BackgroundSleep disturbance is a common feature of depression. However, recent work has found that individuals who are vulnerable to depression report poorer sleep quality compared to their low-risk counterparts, suggesting that sleep disturbance may precede depression. In addition, both sleep disturbance and depression are related to deficits in cognitive control processes. Thus we examined if poor sleep quality predicts subsequent increases in depressive symptoms and if levels of cognitive control mediated this relation.MethodsThirty-five undergraduate students participated in two experimental sessions separated by 3 weeks. Participants wore an actigraph watch between sessions, which provided an objective measure of sleep patterns. We assessed self-reported sleep quality and depressive symptoms at both sessions. Last, individuals completed an exogenous cuing task, which measured ability to disengage attention from neutral and negative stimuli during the second session.ResultsUsing path analyses, we found that both greater self-reported sleep difficulty and more objective sleep stability measures significantly predicted greater difficulty disengaging attention (i.e., less cognitive control) from negative stimuli. Less cognitive control over negative stimuli in turn predicted increased depression symptoms at the second session. Exploratory associations among the circadian locomotor output cycles kaput gene, CLOCK, single nucleotide polymorphism (SNP), rs11932595, as well as sleep assessments and depressive symptoms also are presented.ConclusionsThese preliminary results suggest that sleep disruptions may contribute to increases in depressive symptoms via their impact on cognitive control. Further, variation in the CLOCK gene may be associated with sleep quality.     

Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders

During the intrauterine period a testosterone surge masculinizes the fetal brain, whereas the absence of such a surge results in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other. Sex differences in cognition, gender identity (an individual’s perception of their own sexual identity), sexual orientation (heterosexuality, homosexuality or bisexuality), and the risks of developing neuropsychiatric disorders are programmed into our brain during early development. There is no evidence that one’s postnatal social environment plays a crucial role in gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with any changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other.     

Cognitive performance in young and middle-aged adults with migraine: Investigating the correlation with white matter hyperintensities and psychological symptoms

Introduction

This study aimed to evaluate the cognitive performance of migraine patients with (MwA) and without aura (MwoA) and investigate the correlation of white matter hyperintensities (WMHs) and psychological symptoms with their cognitive test scores.

Association between the 5-HT6 receptor C267T polymorphism and response to antidepressant treatment in major depressive disorder

The purpose of the present study was to determine if a 5-HT6 receptor polymorphism is associated with antidepressant treatment response in major depressive disorder (MDD). Ninety-one patients with MDD, compared with 127 normal control subjects, were evaluated after an 8-week treatment period. An association analysis revealed no differences in genotype and allele distribution between patients with MDD and normal control subjects. However, there were significant differences in the treatment response in some Hamilton Depression Rating Scale (HAM-D) scores (sleep, activity, somatic anxiety, and total) between genotypes. Moreover, the heterozygote group (CT genotype) had significantly better treatment response than the homozygote group (CC + TT genotypes), especially in the somatic-anxiety subcategory and the total score of HAM-D. These findings imply that a 5-HT6 receptor polymorphism (C267T) is associated with treatment response in MDD.     

C-reactive protein,depressive symptoms,and risk of diabetes: Results from the English Longitudinal Study of Ageing (ELSA)

Objectives

Raised levels of C-reactive protein (CRP), an inflammatory biomarker, and depressive symptoms are both independently linked to risk of diabetes. The purpose of this study was to assess the joint association of CRP and depressive symptomatology with diabetes incidence in a representative sample of English people ≥ 50 years old.

Method

Data were from the English Longitudinal Study of Ageing, a prospective study of community-dwelling older adults. The sample was comprised of 4955 participants without self-reported doctor-diagnosed diabetes at baseline. High CRP level was dichotomized as > 3 mg/L. Elevated depressive symptomatology was defined as ≥ 4 using the 8-item Center for Epidemiologic Studies Depression Scale. Incident diabetes was determined based on newly self-reported doctor-diagnosed diabetes. Cox proportional hazard regressions were used to examine the association between CRP and depressive symptoms with incidence of type 2 diabetes.

Results

During approximately 63.2 months of follow-up, 194 participants reported diabetes diagnosis. After adjustment for socio-demographics, lifestyle behaviors, clinical factors, and BMI, the hazard ratio for diabetes was 1.63 (95% CI 0.88–3.01) for people with elevated depressive symptoms only, 1.43 (95% CI 0.99–2.07) for people with high CRP only, and 2.03 (95% CI 1.14–3.61) for people with both high CRP and elevated depressive symptoms.

Conclusion

The presence of both high CRP levels and elevated depressive symptoms was associated with risk of diabetes. Further investigation into this relationship could aid in understanding the mechanisms underlying inflammation, depression, and diabetes.     

Inflammatory biomarkers predict depressive, but not anxiety symptoms during aging: the prospective Sydney Memory and Aging Study

This study addresses the paucity of research on the prospective relationship between a range of inflammatory markers and symptoms of depression and anxiety during aging. In the Sydney Memory and Aging Study, the relationships between remitted depression, current and first onset of symptoms of depression or anxiety (Geriatric Depression Scale and Goldberg Anxiety Scale (GDS, GAS), and markers of systemic inflammation (C-reactive protein (CRP), interleukins-1β, -6, -8, -10, -12, plasminogen activator inhibitor-1 (PAI-1), serum amyloid A, tumor necrosis factor-α, and vascular adhesion molecule-1) were investigated. The sample consists of N=1037 non-demented community-dwelling elderly participants aged 70-90 years assessed at baseline and after 2-years. All analyses were adjusted for gender, age, years of education, total number of medical disorders diagnosed by a doctor, cardiovascular disorders, endocrine disorders, smoking, body mass index, currently using anti-depressants, NSAIDS or statins and diabetes mellitus. The results show a significant linear relationship between increasing levels of IL-6 and depressive symptoms at baseline only, whereas IL-8 was associated with depressed symptoms at baseline and at 2 years follow-up. In addition, IL-8 was associated with first onset of mild to moderate depressive symptoms over 2 years. Logistic regression analyses showed that PAI-1 (OR=1.37, 95% CI=1.10-1.71, p=0.005) was associated with remitted depression. Results for anxiety symptoms were negative. The findings are suggestive of IL-6 and IL-8 being associated with current symptoms and IL-8 being associated with first onset of depressive symptoms, whereas PAI-1 could be regarded as a marker of remitted depression.